This project uses longitudinal PET to address important questions about diagnosis, prognosis, and the mechanisms of cognitive failure in patients with small vessel cerebrovascular disease. The grant uses a longitudinal design and well established methods to address questions that have yielded little progress despite decades of scientific attention. For example, it is presently extremely difficult to determine the relative contributions of ccrebrovascular pathology and Alzheimer's disease in patients with cognitive dysfunction and small subcortical strokes (iacunes). We will test whether or not certain PET findings can be used as in vivo markers for these different pathologies. Very little is known about how to predict cognitive decline in patients with lacunes. Our preliminary data suggest that PET may be useful in defining prognosis and we will explore this application of PET more definitively. These clinical uncertainties reflect underlying confusion about the mechanisms through which tacunes may cause cognitive failure. Damage to subcortical-frontal loops resulting in disconnection of the frontal lobes and attendant cognitive failure is one possible mechanism of ischemic vascular dementia. One goat of this gram is to test this hypothesis. The addition of longitudinal PET and MRI studies to our protocol offers the opportunity to test all of these questions in unique ways that allow stronger attributions of causality. This is a prospective, longitudinal study with an initial sample of 150 subjects. Approximately half of the subjects will have cerebrovascutar disease as revealed by MRI. About 1/3 will be cognitively normal, 1/3 will have mild cognitive impairment, and 1/3 will be demented. Subjects are studied with positron emission tomography (PET) to measure regional brain metabolism, with MRI to measure brain structures, and with neuropsychological tests and behavioral scales to measure symptoms. Difusion tensor imaging is added in this renewal as a potentially superior way of measuring white matter integrity. All subjects will receive annual clinical follow-up evaluations consisting of interim medical history, neurological exams, psychiatric evaluation, and neuropsychologicat testing. Brain imaging studies will be repeated two and four years after the baseline study. This project is expected to yield better understanding of the mechanisms of cognitive failure associated with subcortical stroke, to improve clinical diagnosis, and to improve the prediction of the course of cognitive function in this population.